Circadian rhythms in the auditory system

Abstract: Circadian clocks have been found in numerous cell types and tissues of the body, allowing organisms to coordinate their daily biological functions. They generate cycles of behavioral and physiological processes with a period length of ~24h, which are synchronized to the rotation of the Earth and the subsequent daily changes in illumination, temperature and humidity. The circadian system evolved in order to ensure anticipation and adaptation to these predictable environmental changes, thereby optimizing physiological functions. The current view is that all the cellular clocks of the body are organized in a hierarchical system, which consists of a central master clock and a network of peripheral clocks found in different organs. The circadian organization facilitates temporal control of physiological functions and ensures tissue homeostasis. Prior to this thesis, the consequences of circadian regulation in the auditory system had not been deeply explored. The studies presented here are aiming to investigate the role of the circadian rhythmicity in regulating auditory function. We focused on mechanisms underlying noise sensitivity, involving neurotrophic factors and glucocorticoid hormones. Our results demonstrate that circadian rhythms play a significant role in modulating auditory sensitivity to noise trauma. Mice were found to be more vulnerable to night noise exposure, which triggered permanent hearing loss, whereas day-exposed mice recovered to normal hearing thresholds. This diurnal variation was associated with the presence of a circadian cochlear clock and the circadian control of the brain-derived neurotrophic factor (BDNF). We next found a molecular clock machinery in a central auditory structure, the inferior colliculus (IC), which demonstrated a differential response to day or night noise trauma, and was independent from that of the cochlear clock. Focusing on the cochlear clock, we next identified self-sustained single-cell oscillators originating from sensory and neuronal populations. Cellular clocks were tonotopically arranged, suggesting that networks of individual oscillators may organize circadian rhythms along the length of the cochlea. Finally, we examined the interaction between glucocorticoids and the cochlear clock in regulating the diurnal sensitivity to noise. We found that the absence of circadian glucocorticoid rhythms abolished the greater vulnerability to noise trauma at night, as hearing thresholds recovered completely. This response was linked to glucocorticoid-dependent control of inflammatory cochlear genes. Finally, treatment with the synthetic glucocorticoid dexamethasone at day time, but not at night, protected against noise damage, highlighting the importance of endogenous glucocorticoid rhythms on the effects of otoprotective drugs. In summary, sensitivity to noise insults is greater at specific phases of the circadian cycle, both at behavioral and molecular level and is mediated through complex interaction between circadian clocks, BDNF and glucocorticoids. Overall this thesis is describing a novel feature of the auditory system that would likely have major clinical implications.